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      Insulin-like growth factor 1 receptor stabilizes the ETV6–NTRK3 chimeric oncoprotein by blocking its KPC1/Rnf123-mediated proteasomal degradation

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          Abstract

          Many oncogenes, including chimeric oncoproteins, require insulin-like growth factor 1 receptor (IGF1R) for promoting cell transformation. The ETS variant 6 (ETV6)–neurotrophic receptor tyrosine kinase 3 (NTRK3) (EN) chimeric tyrosine kinase is expressed in mesenchymal, epithelial, and hematopoietic cancers and requires the IGF1R axis for transformation. However, current models of IGF1R-mediated EN activation are lacking mechanistic detail. We demonstrate here that IGF-mediated IGF1R stimulation enhances EN tyrosine phosphorylation and that blocking IGF1R activity or decreasing protein levels of the adaptor protein insulin receptor substrate 1/2 (IRS1/2) results in rapid EN degradation. This was observed both in vitro and in vivo in fibroblast and breast epithelial cell line models and in MO91, an EN-expressing human leukemia cell line. Stable isotope labeling with amino acids in cell culture (SILAC)–based MS analysis identified the E3 ligase RING-finger protein 123 (Rnf123, more commonly known as KPC1) as an EN interactor upon IGF1R/insulin receptor (INSR) inhibitor treatment. KPC1/Rnf123 ubiquitylated EN in vitro, and its overexpression decreased EN protein levels. In contrast, KPC1/Rnf123 knockdown rendered EN resistant to IGF1R inhibitor–mediated degradation. These results support a critical function for IGF1R in protecting EN from KPC1/Rnf123-mediated proteasomal degradation. Attempts to therapeutically target oncogenic chimeric tyrosine kinases have traditionally focused on blocking kinase activity to restrict downstream activation of essential signaling pathways. In this study, we demonstrate that IGF1R inhibition results in rapid ubiquitylation and degradation of the EN oncoprotein through a proteasome-dependent mechanism that is reversible, highlighting a potential strategy for targeting chimeric tyrosine kinases in cancer.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          10 August 2018
          14 June 2018
          : 293
          : 32
          : 12502-12515
          Affiliations
          From the []Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada,
          the [** ]Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada,
          the [§ ]Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan, 812-8582,
          the []Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97239, and
          the []Lady Davis Institute for Medical Research SMBD, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
          Author notes
          [2 ] To whom correspondence should be addressed: Dept. of Molecular Oncology, British Columbia Cancer Research Centre, 675 W. 10th Ave, Vancouver, BC V5Z 1L3, Canada. Tel.: 604-675-8202; Fax: 604-675-8218; E-mail: psor@ 123456mail.ubc.ca .
          [1]

          These authors share equal authorship.

          Edited by Jeffrey E. Pessin

          Author information
          https://orcid.org/0000-0003-2985-7115
          Article
          PMC6093223 PMC6093223 6093223 RA117.000321
          10.1074/jbc.RA117.000321
          6093223
          29903916
          e2d435f0-b1c3-4e2a-8ce8-e57212256e74
          © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
          History
          : 12 October 2017
          : 7 June 2018
          Categories
          Protein Synthesis and Degradation

          fusion protein,ubiquitylation (ubiquitination),Non-receptor tyrosine kinase (nRTK),insulin-like growth factor (IGF),oncogene

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